JPH0770112A - Tetrazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new tetrazole derivative effective for both immediate reaction and delayed reaction of asthma with high safety, having excellent antiallergic action and antihistaminic action. CONSTITUTION:A compound of formula 1 [A is CH=CH, CH2-CH2, CH2O, O, S or in the case wherein A is not linked to aromatic ring, A is H bonded to each aromatic ring; V is CH=CH or S; X and Y are an alkoxy, a halogen or H; (a) W is bond, Z is C or methine, B is bonded to Z or OH, (b) W is a bond, Z id N, B is H or (c) W is O, Z is methyl, B is H; (p) is 2 or 3; (n) is 1-6] or its pharmacologically permissible salt such as 4-dibenzo[a, d]cyclohepten-5-ylidine-1-[3-(1H-tetrazol-5-yl)propyl]piperidine. This compound is obtained by reacting a compoundf of formula 2 with a compound of formula 4 in the presence of a base to give a compound of formula 3 and reacting the compound of formula with a metal salt of hydrogen azide in the presence of a trialkyltin azide.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel tetrazole derivative or a salt thereof, and an antihistamine, an antiallergic agent and an asthma treatment containing the same, having excellent antihistamine and antiallergic activity and having less central action. Regarding agents. The compounds of the present invention are also effective as therapeutic agents for rhinitis, nephritis, atopic dermatitis and psoriasis.

[0002]

2. Description of the Related Art Conventionally, many benzhydryl derivatives have been synthesized and various pharmacological actions including antiallergic action have been investigated. European Patent 82-870006 and Japanese Patent Laid-Open No. 3-246287 disclose certain carboxylic acid derivatives,
WO93 / 02062 describes certain tetrazole derivatives. Further, JP-A-4-234359 and JP-A-4-234387 describe piperazine derivatives. However, these compounds have drawbacks in that they are not yet sufficiently effective, and have problems of centrally suppressing action such as drowsiness and sedation. Further, the conventional compounds were able to suppress the immediate reaction of asthma, but could not sufficiently suppress the delayed reaction. Therefore, currently, steroids are used for the treatment of late-onset type asthma, but steroids also have side effect problems. Another drawback of conventional antihistamines is that they have an anticholinergic effect that contributes to side effects such as dry mouth and mydriasis. Various studies have been conducted so far to overcome these drawbacks, but it cannot be said that sufficiently satisfactory results have been obtained yet.

[0003]

The object of the present invention is to have a further excellent antiallergic action and antihistamine action,
It is to create a compound that is effective for both immediate reaction and late reaction of asthma and has high safety.

[0004]

Means for Solving the Problems In view of the above circumstances, the present inventors have synthesized a number of tetrazole derivatives and studied their antihistamine, antiallergic action, and central action. The tetrazole derivative represented by (1) or a salt thereof has a strong antihistamine action and an antiallergic action, and in addition, as with steroids, it can sufficiently suppress the late-onset reaction of asthma and has a central depressant action. They found that they were weak and completed the present invention.

That is, the present invention uses the following formula (1):

[Chemical 3] [In the formula, A _{-CH = CH -, - CH 2} -CH 2 -, - C
H ₂ O-, an oxygen atom or a sulfur atom, or when A is not linked to an aromatic ring, A represents a hydrogen atom bonded to each aromatic ring; V represents -CH = CH- or a sulfur atom. Xa and Y each independently represent an alkoxy group, a halogen atom or a hydrogen atom; (a) W is a bond, Z is a carbon atom or methine, B is a bond with Z or represents a hydroxy group, Alternatively, (b) W is a bond, Z is a nitrogen atom, B is a hydrogen atom, or (c) W is an oxygen atom, Z is methine, and B is a hydrogen atom; p is an integer of 2 to 3; And n is 1
A tetrazole derivative represented by the formula [4] or a pharmacologically acceptable salt thereof, and an antihistamine, an antiallergic agent and an asthma therapeutic agent containing the same as an active ingredient.

The present invention includes all isomers although some of the present compounds have optical isomers.

The salts of the compounds of the present invention include medically acceptable salts such as hydrochloric acid, nitric acid, sulfuric acid, maleic acid, fumaric acid, oxalic acid, citric acid, hydrobromic acid, tartaric acid and succinic acid. , Sulfamic acid, mandelic acid, malonic acid, phosphoric acid or the like, or sodium salt, potassium salt, lithium salt, calcium salt, zinc salt or the like basic salt, but it is particularly limited. There is no such thing.

The compound (1) of the present invention can be produced, for example, as follows.

Reaction formula 1)

[Chemical 4] (In the formula, V, W, X, Y, Z, p, n, A and B have the same meaning as described above, and L represents a halogen atom.) That is, the compound represented by the general formula (2) By reacting the compound represented by the general formula (4) in the presence of a base, the compound represented by the general formula (3) is produced. The above reaction is preferably carried out in a solvent that does not affect the reaction. Examples of the solvent include water, esters such as methyl acetate and ethyl acetate; ethers such as diethyl ether, diisopropyl ether, terrahydrofuran, dioxane; ketones such as acetone and methyl ethyl ketone; halogenated hydrocarbons such as dichloromethane and chloroform. Aromatic hydrocarbons such as benzene, toluene and xylene; other acetonitrile, dimethylsulfoxide, dimethylformamide and the like can be used alone or in combination of two or more. The reaction temperature will differ depending on the raw materials used, but can be carried out between 0 ° C and 200 ° C. Further, a base catalyst is generally effective for the progress of the reaction, but it is not always necessary. As the base, caustic potash, caustic soda, potash carbonate, sodium carbonate, triethylamine, pyridine, tributylammonium hydroxide and the like are preferable. Further, the compound of the general formula (3) is produced by reacting a metal salt of hydrogen azide such as sodium azide and potassium azide with the presence of trialkyltin azide, trialkylsilicon azide or ammonium salt. You can do it. The above reaction is preferably carried out in a solvent that does not affect the reaction. Xylene,
Toluene, benzene, terrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone and the like can be used alone or in combination of two or more. The reaction temperature varies depending on the raw materials used, but is 0 ° C to 2
It can be performed between 00 ° C.

Some compounds represented by the structural formula (2) are known, but new ones are represented by the following reaction formula 2),
It can be synthesized by the reaction shown in 3) or 4).

Reaction formula 2)

[Chemical 5] The conversion of (5) to (6) can be carried out by reacting (5) with a substituted phenylmagnesium halide or a substituted phenyllithium. The conversion from (6) to (7) can be carried out by using a catalyst (platinum oxide, palladium carbon, palladium, etc.) in hydrogen under normal pressure or pressure. Further, the conversion of (7) to (2a) can be easily obtained under acidic conditions, for example, acetic acid-sulfuric acid, or general dehydration reaction conditions, for example, toluenesulfonic acid-benzene. Reaction formula 3)

[Chemical 6] The conversion of (9) to (10) can be carried out using titanium in a low oxidation state. The solvent may be any solvent inert to the reaction, but is preferably an ether solvent such as dioxane, tetrahydrofuran, dimethoxytan or ether.

Reaction formula 4)

[Chemical 7] The conversion example from (8) to (12) can be performed by a known method. The conversion from (12) to (13) can be easily carried out under acidic conditions, for example, acetic acid-sulfuric acid, or general dehydration reaction conditions, for example, toluenesulfonic acid-benzene. Also, from (13) to (2
The conversion to b) can be carried out by reacting (13) with an alkyl chloroformate to form a carbamate body, followed by alkali hydrolysis.

The following are specific examples of the compound of the present invention.

(Compound 1) 4-dibenzo [a, d] cycloheptene-5-ylidene-1- [3- (1H-tetrazol-5-yl) propyl] piperidine (Compound 2) 4-dibenzo [a, d] Cycloheptene-5-ylidene-1- (1H-tetrazol-5-ylmethyl) piperidine (Compound 3) 4-dibenzo [a, d] cycloheptene-5-ylidene-1- [4- (1H-tetrazole-5
-Yl) butyl] piperidine (Compound 4) 4- (10,11-dihydrodibenzo [a, d] cycloheptene-5-ylidene) -1- [3
-(1H-tetrazol-5-yl) propyl] piperidine (Compound 5) 4- (6H-dibenzo [b, e] oxepin-11-ylidene) -1- [3- (1H-tetrazol-5-yl) propyl ] Piperidine (Compound 6) 4- [bis (4-fluorophenyl) methylene] -1- [3- (1H-tetrazol-5-yl) propyl] piperidine (Compound 7) 4- (phenyl-2-thienylmethylene) -1- [3- (1H-tetrazol-5-yl) propyl] piperidine (Compound 8) 4-Benzhydrylylidene-1- [3
-(1H-Tetrazol-5-yl) propyl] piperidine (Compound 9) 4-Benzhydrylylidene-1- [5
-(1H-tetrazol-5-yl) pentyl] piperidine (Compound 10) α, α-diphenyl-N- [3- (1
H-tetrazol-5-yl) propyl] piperidine-
4-ylmethanol (Compound 11) 4- [bis (4-methoxyphenyl)
Methylene] -1- [4- (1H-tetrazol-5-yl) butyl] piperidine (Compound 12) 4-dibenzo [a, d] cycloheptene-5-ylidene-1- [5- (1H-tetrazole-
5-yl) pentyl] piperidine (Compound 13) 4-xanthene-9-ylidene-1-
[3- (1H-Tetrazol-5-yl) propyl] piperidine (Compound 14) 4-Thioxanthene-9-ylidene-
1- [3- (1H-tetrazol-5-yl) propyl] piperidine (Compound 15) 1-Benzhydryl-4- [3- (1
H-tetrazol-5-yl) propyl] piperazine (Compound 16) 1-benzhydryl-4- [3- (1
H-tetrazol-5-yl) propyl]-[1,4]
Diazepane (Compound 17) 1-Benzhydryl-4- (1H-tetrazol-5-ylmethyl) piperazine (Compound 18) 1-Benzhydryl-4- [4- (1
H-tetrazol-5-yl) butyl] piperazine (Compound 19) 1-[(4-chlorophenyl) phenylmethyl] -4- [3- (1H-tetrazol-5-yl) propyl] piperazine (Compound 20) 1- [Bis (4-fluorophenyl)
Methyl] -4- [3- (1H-tetrazol-5-yl) propyl] piperazine (Compound 21) 4-Benzhydryloxy-1- [3
-(1H-Tetrazol-5-yl) propyl] -piperidine (Compound 22) 4-[(4-chlorophenyl) phenylmethoxy] -1- [3- (1H-tetrazole-5-
Iyl) propyl] piperidine (Compound 23) 4- [bis (4-fluorophenyl)
Methoxy] -1- [3- (1H-tetrazol-5-yl) propyl] piperidine (Compound 24) 4-[(4-chlorophenyl) phenylmethoxy] -1- [4- (1H-tetrazole-5-
(Compound 25) 4- (phenyl-p-chlorophenylmethylene) -1- [3- (1H-tetrazol-5-yl) propyl] piperidine (Compound 26) 4- (10,11-dihydrodibenzo) [A, d] cycloheptan-5-yl) -1- [3-
(1H-Tetrazol-5-yl) propyl] piperazine (Compound 27) 4- (10,11-dihydrodibenzo [a, d] cycloheptan-5-yl) -1- [4-
(1H-Tetrazol-5-yl) butyl] piperazine (Compound 28) 4- (6H-dibenzo [b, e] oxepin-11-yl) -1- [3- (1H-tetrazol-5-yl) propyl] Piperazine (Compound 29) 4- (dibenzo [a, d] cyclohepten-5-yl) -1- [3- (1H-tetrazole-
5-yl) propyl] piperidine (Compound 30) 4- (dibenzo [a, d] cyclohepten-5-yl) -1- [4- (1H-tetrazole-
5-yl) butyl] piperidine (Compound 31) 4- (6H-dibenzo [b, e] oxepin-11-yl) -1- [4- (1H-tetrazol-5-yl) butyl] piperazine (Compound 32) 4-[(4-chlorophenyl) phenylmethylene] -1- [4- (1H-tetrazole-5-
Iyl) butyl] piperidine (Compound 33) 4-[(4-chlorophenyl) phenylmethylene] -1- [3- (1H-tetrazole-5-
Il) propyl] piperidine The compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be mixed with a pharmaceutically acceptable auxiliary agent to prepare a preparation for oral administration or parenteral administration. .

Examples of solid preparations for oral administration include tablets, powders, granules, capsules and the like. The compound (I) of the present invention can be used as a suitable additive such as lactose, mannitol, corn starch and crystals. Excipients such as cellulose; binders such as cellulose derivatives, gum arabic and gelatin;
It is produced by appropriately combining a disintegrating agent such as carboxymethylcellulose calcium; a lubricant such as talc and magnesium stearate. Further, these solid preparations can be used as an enteric agent by using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer.

Examples of the liquid preparations for oral administration include emulsions, solutions, suspensions, syrups and elixirs. The compound (I) of the present invention is generally used as an inert diluent. It is produced by combining with an agent such as purified water, ethanol and the like. In addition to the inert diluent, this composition may contain auxiliary agents such as wetting agents and suspending agents, sweetening agents, flavoring agents, aromatic agents, preservatives and the like. In addition, an aerosol agent manufactured by a known method can be used.

Examples of the preparation for parenteral administration include injectable solutions, which are produced by combining the compound (I) of the present invention with water, ethanol, glycerin, conventional surfactants and the like. Furthermore, an inhalant, a liquid for external use, an eye drop, a nasal drop, a coating agent such as an ointment and the like which are prescribed by a known method can be used.

The dose of the compound (I) of the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method, administration period and the like, but is usually 1 to 500 mg / day, particularly 5 to 50 mg / day. Orally administered 1 to 3 times daily or 0.
It is preferable to administer parenterally once to several times a day in the range of 1 to 500 mg / day.

Next, the pharmacological actions of representative compounds of the compound (I) of the present invention and salts thereof will be described.

Test Examples Test Example 1: Antihistamine action in the isolated bronchi of guinea pigs Male Hartley guinea pigs (body weight 300-60)
(0 g) was anesthetized with ether and killed by exsanguination, and then the bronchus was immediately removed to prepare a sample. The sample is a Magnus tube filled with 20 ml of Tyrode's solution (30 ° C, 95% O ₂ , 5% CO ₂ )
Suspended with an initial load of 1 g. The tension generated by drug administration of this sample was measured isometrically via a tension transducer. The effect of the test compound on the contraction caused by 10 ⁻⁵ mol of histamine was observed when the sample became stable after 30 to 60 minutes after the suspension. From this, the dose-effect relationship of the test compound was examined, and its 50% inhibitory concentration (IC ₅₀
Value) was calculated. The results are shown in Table 1 below.

As a reference compound, cetirizine (ce
tirizine: the compound described in JP-A No. 57-149282), the IC ₅₀ was determined to be 2.40 μM.

[0022]

[Table 1] Test Example 2: Anti-allergic action An anti-DNP-As (Dinitrophenyl conjugated A) prepared by cutting the back of a male SD rat (body weight 150 to 250 g) in advance with a shaved hair and diluting it to an appropriate concentration with saline.
0.1 ml of scaris) IgE serum was injected intradermally on the back to passively sensitize. After 48 hours 2.5 ml DNP-As
1 ml of a 0.5% Evans Blue physiological saline solution containing 300 μM was intravenously administered. Thirty minutes later, exsanguination was lethal under anesthesia, and the blue spot on the back skin was punched out with a leather punch, and the method of Harada et al. (Allergy, l5, l-7 (196
The amount of leaked dye was measured according to 6)). The amount of leakage dye due to passive sensitization anaphylaxis [PCA] was determined by subtracting the amount of leakage dye at the physiological saline administration site from the amount of leakage dye at the PCA site. The test compound was suspended in 0.5% methylcellulose, and 10 mg / 4 ml / kg was orally administered 1 hour before the antigen administration. The efficacy of the test compound was judged by the rate of suppression of the amount of leaked pigment (antiallergic effect). The results are shown in Table 2 below.
Shown in.

[0023]

[Table 2] Test Example 3: Toxicity test Four to five-week-old ICR mice were used as one group consisting of five mice.

After suspending the compound of each Experimental Example in a physiological saline solution of 0.5% methylcellulose, 100 m of each was suspended.
It was intraperitoneally administered at a dose of g / kg and observed for 7 days. The control compound, diphenhydramine, died at 100 mg / kg in all cases, but no death case due to the toxicity of the compound of the present invention was observed.

Test Example 4: Sleep extension effect ICR mice aged 4 to 5 weeks were used as one group consisting of 10 mice.

The compound of each experimental example was suspended in a 0.5% methylcellulose solution and orally administered at a dose of 25 mg / kg. 1 hour later pentobarbital 40
Coma was induced by intraperitoneal administration of mg / kg. Onset of coma was considered from the moment when the animal lost its upright reflex and lay down back, and end of coma was considered from the moment the animal regained such reflex.

Terfenadine, which is an antiallergic agent similar to the compound of the present invention and is known to have a short hypnotic prolonging effect, was used as a control compound. The data obtained are presented as the% increase in sleep time in the treated animals compared to the negative control (no compound given) animals. The results are shown in Table 3 below.

[0028]

[Table 3] By the above test, it was confirmed that the compound of the present invention had a small central inhibitory effect.

Test Example 5 Leukocyte Infiltration Inhibition Test in Guinea Pig Alveolar American Review of Respiratory Diseases 1990 Volume 142 Pages 680-685 (A
American Review of Respiratory Disease, 142: 680-68
5, 1990).

Hartley guinea pigs (5 weeks old) were mixed with rabbit anti-ovalbumin (OA) serum (0.25 ml / ani).
(mal) was intravenously injected and passively sensitized for 48 hours. An antihistamine (mepyramine, 10 mg) was intraperitoneally administered to prevent asthma death due to immediate asthmatic reaction (IAR), and 0.25% OA antigen was exposed for 10 minutes by an ultrasonic nebulizer. After 24 hours, bronchoalveolar (BAL) lavage was performed under pentobarbital anesthesia, and the total number of white blood cells infiltrating the respiratory tract was measured with a call counter. In addition, a preparation sample was prepared, the ratio of mononuclear cells, eosinophils, and neutrophils in the bronchoalveolar lavage fluid (BALF) was examined, and each number was calculated from total white blood cells. 30 mg of each compound is Twee
The cells were suspended in 0.5% methylcellulose containing n80 and orally administered 1 hour before and 6 hours after exposure to the OA antigen. The inhibitory rate of leukocyte infiltration into the bronchoalveolar lavage fluid of the compound-administered group was 0 after exposure to OA, and the infiltrated leukocyte count of the group not administered with OA antigen was 0.
Was calculated as That is, it was calculated by the following formula.

[0031]

[Formula 1] The results obtained in the above test are shown in Table 4 below.

[0032]

[Table 4] This test showed that the compounds of the present invention are also effective for allergic late-onset asthma symptoms. The drugs such as oxatomide, ketotifen, and diphenhydramine shown in Test Examples 1 to 3 were ineffective in this test. In addition,
Values were also shown for cetirizine as a control compound. No clear effect was found in the control drug compared to the compound of the invention.

Test Example 6 Anaphylaxis Airway Contraction Response Inhibition Test The test was carried out as follows according to the overflow method of Konzett and Roessler.

Hartley guinea pigs (5 weeks old) were mixed with rabbit anti-ovalbumin (hereinafter abbreviated as OA) serum (0.1 m).
(1 / animal) was intravenously injected and passively sensitized for 48 hours. Urethane (1.5 mg / kg) anesthesia, after tracheal cannula insertion,
Wearing a respirator (10ml / kg / stroke, 60stroke / m
in.) forcing breathing and immobilizing with Galamine triethiodide (5 mg / kg; ip). Approximately 1 hour later, 1 mg / kg of the drug was intravenously injected, and further 15 minutes later, antigen administration (ovalbumin, 0.10 mg / kg, intravenous injection) induces an anaphylactic airway contraction reaction. Anaphylactic airway constriction occurs, increasing airway resistance and spilling air from the ventilator. The amount of air that overflows at this time
(Ventilation Over Flow Volume (hereinafter VOFV)) was measured over time. The anaphylactic airway of the drug administration group, where the integrated value of the peak value of VOFV and the value between 0 and 30 minutes of OA administration is 0% for the group with OA administration and no drug administration and 100% for the value before OA administration. It was calculated as the shrinkage inhibition rate.
That is, the suppression rate of the peak was calculated by the following formula and the value was expressed in%.

[0035]

[Formula 2] The inhibition rate of the integrated value during 30 minutes of antigen administration was calculated by the following formula and the value was expressed in%.

[0036]

[Formula 3] The results obtained are shown in Table 5 below.

[0037]

[Table 5] From the results of tests 1 to 6 described above, it was revealed that the compound of the present invention has excellent antihistamine action and antiallergic action, and exhibits a remarkable effect on both late-onset and immediate-type asthma. In particular, compounds 21 and 22 not only strongly suppress the immediate bronchoconstriction that is an early symptom of asthma, but also strongly suppress the delayed infiltration of white blood cells into the lung, and are therefore the most preferable compounds. it can. further,
From such a pharmacological effect, the compound of the present invention is a therapeutic agent for rhinitis,
It is also useful as a therapeutic agent for nephritis, a therapeutic agent for atopic dermatitis and a therapeutic agent for psoriasis.

The present invention will be described in more detail with reference to examples below, but the scope of the present invention is not limited thereby.

Example 1 4-Dibenzo [a, d] cycloheptene-5-ylidene-1- [3- (1H-tetrazol-5-yl) propyl] piperidine

[Chemical 8] 4-dibenzo [a, d] cycloheptene-5-ylidenepiperidine (5 g, 18.3 mmol), bromobutyronitrile (2.7
g, 18.3 mmol) and potassium carbonate (10 g) were suspended in DMF,
The mixture was stirred at 100 ° C for 3 hours. The reaction solution was poured into water, extracted with ether, dried and concentrated under reduced pressure to obtain oily 4- (4-dibenzo [a, d] cycloheptene-5-ylidenepiperidin-1-yl) butyronitrile.

IR (nujol): cm ^-1 : 2250,1490,14
35,1135 Sodium azide (5.9 g, 0.92 mmol) and ammonium chloride (4.9
g, 0.92 mmol) was added and the mixture was stirred overnight at 110 ° C. After stirring,
The mixture was poured into water to adjust the pH to 6, extracted with chloroform, dried, and then concentrated under reduced pressure to about 30 ml. By allowing this liquid to stand, the precipitated crystals were collected to obtain 4.5 g of the title compound as a powder. Melting point (decomposition point): as 134-139 ° C. Elemental Analysis _{C 24 H 25 N 5 · 2H} 2 O (%) MS (m / z): 384 (M + H), (SIMS) IR (nujol): cm ^-1 : 1300,1160,1080,990,960,9
50,880 NMR (DMSO-d ₆ ) δppm: 7.37 (4H, m), 7.28 (2
H, d, J = 7.3), 6.96 (2H, s), 2.85 (2H, t, J = 7.2), 2.66
(2H, t, J = 7.2), 2.46 (2H, m), 2.27 (4H, m), 2.01 (2H,
m), 1.86 (2H, m) Example 2 4-dibenzo [a, d] cycloheptene-5-ylidene-1- (1H-tetrazol-5-ylmethyl) piperidine

[Chemical 9] 4-Dibenzo [a, d] cycloheptene-5-ylidenepiperidine (3.8 g, 14 mmol), bromoacetonitrile (1.68 g, 14 mmol), and potassium carbonate (5.5 g) were suspended in DMF and the suspension was heated at 100 ° C for 3 hours. It was stirred. The reaction mixture was poured into water, extracted with ether, dried and concentrated under reduced pressure to give oily 4- (4-dibenzo [a, d] cycloheptene-5-ylidenepiperidin-1-yl) acetonitrile. Sodium azide (2.99 g, 40.2 mmol) and triethylammonium chloride (2.77 g, 20.1 mmol) were added to the above compound without further purification, and methylpyrrolidone (5
0 ml) and stirred at 150 ° C. for 3 hours. After stirring, pour in water to adjust pH to 6, extract with chloroform, dry,
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and crystallized from ethyl acetate to give 3.19 g.
(62%) of the title compound was obtained.

Melting point: 231-233 ° C. MS (m / z): 356 (M + H), 277, 185 IR (nujol): cm ⁻¹ : 1630,1305,1270,1160,102
The following compounds were synthesized using a similar method.

Example 3 4-Dibenzo [a, d] cycloheptene-5-ylidene-1- [4- (1H-tetrazol-5-yl) butyl] piperidine

[Chemical 10] Bubble MS (m / z): 398 (M + H), 286, 185 (SIMS) IR (nujol): cm ^-1 : 1650,1550,1300,1250,950,
800,760 NMR (DMSO-d ₆ ) δppm: 7.49 (4H, m), 7.40 (2
H, m), 7.31 (2H, d, J = 8.3), 7.08 (2H, s), 2.95 (2H, t, J
= 7.2), 2.71 (2H, t, J = 7.2), 2.49 (2H, t, J = 6.9), 2.37
(4H, m), 2.12 (2H, m), 1.77 (2H, m), 1.58 (2H, m) Example 4 4- (10,11-dihydrodibenzo [a, d] cycloheptene-5-ylidene)- 1- [3- (1H-tetrazol-5-yl) propyl] piperidine

[Chemical 11] Bubble MS (m / z): 386 (M + H), (SIMS) IR (nujol): cm ^-1 : 1640,1295,950,750 NMR (DMSO-d ₆ ) δppm: 7.0-7.4 (8H, m) , 4.03
(1H, s), 3.89 (2H, m), 2.85 (2H, t, J = 7), 2.72 (2H, m),
2.44 (4H, m), 1.84 (2H, quintet, J = 7) Example 5 4- (6H-dibenzo [b, e] oxepin-11-ylidene) -1- [3- (1H-tetrazole-5- Il) propyl] piperidine

[Chemical 12] Melting point (decomposition point): 192-196 ° C MS (m / z): 388 (M + H), 290 (SIMS) IR (nujol): cm ^-1 : 2700,1550,1290,1220,760 NMR (DMSO- d ₆ ) δppm: 7.50 (1H, d, J = 6), 7.
35 (2H, m), 7.0-7.3 (3H, m), 6.84 (1H, t, J = 7), 6.73
(1H, d, J = 7), 3.1-3.6 (6H, m), 2.99 (4H, m), 2.88 (2H,
m), 2.79 (2H, m), 2.13 (2H, quintet, J = 7) Example 6 4- [bis (4-fluorophenyl) methylene] -1-
[3- (1H-tetrazol-5-yl) propyl] piperidine

[Chemical 13] Colorless powder Melting point: 185-187 ° C (ethyl acetate) MS (m / z): 396 (M + H), 298, 106 (SIMS) IR (nujol): cm ^-1 : 1600, 1500, 1450, 1410, 122
0,1160,840 NMR (DMSO-d ₆ ) δppm: 7.21 (8H, m), 2.96 (2
H, t, J = 7.3), 2.68 (4H, t, J = 5.3), 2.59 (4H, t, J = 2.0),
2.35 (2H, t, J = 5.3), 1.98 (2H, m) Example 7 4- (phenyl-2-thienylmethylene) -1- [3-
(1H-tetrazol-5-yl) propyl] piperidine

[Chemical 14] Melting point: 215-219 ° C MS (m / z): 366 (M + H), 268 (SIMS) IR (nujol): cm ^-1 : 1405,1340,1080,970,830,7
05 NMR (DMSO-d ₆ ) δppm: 7.57 (1H, dd, J = 1.0,5.
3), 7.43 (3H, m), 7.26 (2H, m), 7.12 (1H, dd, J = 4.9,3.
3), 6.97 (1H, m), 3.00 (2H, t, J = 7.2), 2.62 (8H, m),
2.35 (2H, t, J = 5.3), 2.00 (2H, m) Example 8 4-Benzhydrylylidene-1- [3- (1H-tetrazol-5-yl) propyl] piperidine

[Chemical 15] Colorless powder Melting point: 223-226 ° C (ethyl acetate) MS (m / z): 360 (M + H), 262, (SIMS) IR (nujol): cm ^-1 : 1600, 1500, 1450, 1410, 122
0,1160,840 NMR (DMSO-d ₆ ) δ: 7.21 (10H, m), 2.96 (2H,
t, J = 7.3), 2.68 (4H, t, J = 5.3), 2.59 (4H, t, J = 2.0), 2.
35 (2H, t, J = 5.3), 1.98 (2H, m) Example 9 4-Benzhydrylylidene-1- [5- (1H-tetrazol-5-yl) pentyl] piperidine

[Chemical 16] Bubble MS (m / z): 388 (M + H), (SIMS) IR (nujol): cm ^-1 : 1600,1500,1450,1410,122
0,1160,840 NMR (DMSO-d ₆ ) δppm: 7.2-7.6 (10H, m), 3.0
1 (2H, t, J = 7), 2.81 (4H, t, J = 7), 2.64 (4H, m), 2.48
(2H, m), 1.86 (2H, quintet, J = 7), 1.66 (2H, quintet, J =
7), 1.48 (2H, quintet, J = 7) Example 10 α, α-diphenyl-N- [3- (1H-tetrazol-5-yl) propyl] piperidin-4-ylmethanol

[Chemical 17] Melting point (decomposition point): 250 ° C or higher MS (m / z): 378 (M + H), 133,105 IR (nujol): cm ^-1 : 1660, 1170, 1100, 1060 NMR (DMSO-d ₆ ) δppm: 7.51 (4H, d, J = 7.6),
7.27 (4H, t, J = 6.9), 7.14 (2H, dd, J = 7.6,6.9), 3.20
(2H, d, J = 11.2), 2.79 (4H, m), 2.50 (8H, m), 1.92 (2H,
m), 1.63 (1H, m), 1.35 (2H, d, J = 12.6) Example 11 4- [bis (4-methoxyphenyl) methylene] -1-
[4- (1H-tetrazol-5-yl) butyl] piperidine

[Chemical 18] Melting point: 120-123 ° C MS (m / z): 434 (M + H), 322, 121 NMR (DMSO-d ₆ ) δppm: 6.95 (4H, d, J = 8.6),
6.85 (4H, d, J = 8.6), 3.72 (6H, s), 2.84 (2H, t, J = 7.2),
2.55 (4H, brs), 2.50 (4H, brs), 2.30 (2.50, m), 1.69
(2H, m), 1.50 (2H, m) Example 12 4-Dibenzo [a, d] cycloheptene-5-ylidene-1- [5- (1H-tetrazol-5-yl) pentyl] piperidine

[Chemical 19] Colorless powder Melting point: 193-197 ° C MS (m / z): 412 (M + H), (SIMS) IR (nujol): cm ^-1 : 1650,1550,1300,1250,950,
800,760 NMR (DMSO-d ₆ ) δppm: 7.51 (4H, m), 7.43 (2
H, m), 7.33 (2H, d, J = 8.3), 7.10 (2H, s), 2.94 (2H, t, J
= 7.2), 2.75 (2H, t, J = 7.2), 2.40 (4H, t, J = 6.9), 2.16 (4
H, m), 1.80 (2H, m), 1.59 (2H, m), 1.44 (2H, m) Example 13 4-xanthene-9-ylidene-1- [3- (1H-tetrazol-5-yl) Propyl] piperidine

[Chemical 20] Melting point: 250 ° C or higher (ethyl acetate) MS (m / z): 374 (M + H), (SIMS) IR (nujol): cm ^-1 : 2450,1590,1550,1250,120
0,1150,1100,1060,1050 NMR (DMSO-d ₆ ) δppm: 7.2-7.7 (8H, m), 2.8-
3.6 (12H, m), 2.25 (2H, quintet, J = 7) Example 14 4-thioxanthene-9-ylidene-1- [3- (1H
-Tetrazol-5-yl) propyl] piperidine

[Chemical 21] Melting point 250 ° C or higher MS (m / z) :, 390 (SIMS) NMR (DMSO-d ₆ ) δppm: 7.2-7.7 (8H, m), 2.8-
3.6 (12H, m), 2.26 (2H, quintet, J = 7) Example 15 1-Benzhydryl-4- [3- (1H-tetrazol-5-yl) propyl] -piperazine

[Chemical formula 22] Benzhydrylpiperazine (10.62g, 42mmol), 4-bromobutyronitrile (6.23g, 42mmol), and potassium carbonate (1
1.6 g, 84 mmol) was suspended in acetonitrile (200 ml) and stirred overnight at 60 ° C. After cooling the reaction solution, the inorganic substances are filtered off,
Acetonitrile was concentrated under reduced pressure to give oil 4- (4-benzhydrylpiperazin-1-yl) butyronitrile (13.4
g, 99%) was obtained.

MS (m / z) SI-MS, Pos: 319 (M + H) IR (Neat), cm ^-1 : 2250 (nitrile), 1490, 1445 4- (4-benzhydrylpiperazine-1- (Il) butyronitrile without further purification of DMF (150 m
1), ammonium chloride (6.74 g) and sodium azide (8.19 g) were added, and the mixture was stirred at 90 ° C. for 48 hours.
The reaction mixture was poured into 300 ml of water, and ethyl acetate (200
(ml), the ethyl acetate extract was removed, and the aqueous layer was extracted twice with chloroform (200 ml). The chloroform layer was taken, dried over magnesium sulfate, and then concentrated under reduced pressure to a solution amount of about 30 ml and left to stand. The precipitated crystals were filtered to obtain a powdery title compound (5.5 g). Decomposition point 218 ° C MS (m / z) SI-MS, Pos: 363 (M + H) Elemental analysis C ₂₁ H ₂₆ N _{As 6} (%) IR (nujol), cm ^-1 : 1405, 1310,1192,1087 ¹ H-NMR (DMSO-d ₆ ) δppm: 50 ℃, 1.84 (2H, m), 2.2-3.7
(10H, m), 2.85 (2H, m), 4.27 (1H, s), 5.60 (2H, brs, H
₂ O), 7.0-7.4 (10H, m) ¹³ C-NMR (DMSO-d ₆ ) δppm: 50 ° C, 156.07, 142.48, 12
8.16, 127.35, 126.54,95.29, 74.83, 56.41, 52.42, 5
0.95, 23.80, 20.87 Example 16 1-Benzhydryl-4- [3- (1H-tetrazole-5-
Il) propyl]-[1,4] diazepan

[Chemical formula 23] It was synthesized via a nitrile as in Example 1. Melting point 172-175 ° C (Ethyl acetate) MS (m / z) SI-MS: 377 (M + H) Elemental analysis As C ₂₂ H ₂₈ N ₆ 1 / 2H ₂ O (%) IR (nujol) cm ^-1 : 1600,1495,1405,1330,1320 ¹ H-NMR (DMSO-d ₆ ) δppm: 21.8 ° C, 1.81 (2H, m), 1.94
(2H, m), 2.4-2.7 (10H, m), 3.13 (2H, m), 4.71 (1H,
s), 7.0-7.4 (10H, m) Example 17 1-Benzhydryl-4- (1H-tetrazol-5-ylmethyl) piperazine

[Chemical formula 24] Melting point 179-182 ° C (Ethyl acetate) MS (m / z) SI-MS, Pos: 335 (M + H) Elemental analysis As C ₁₉ H ₂₂ N ₆ (%) IR (nujol) cm ^-1 : 2450,1600,1490,1410,1340,1190,10
80,1040,970,750,710 Example 18 1-Benzhydryl-4- [4- (1H-tetrazole-5-
Ill) butyl] -piperazine

[Chemical 25] Melting point 67-68 ℃ Elemental analysis As C ₂₂ H ₂₈ N ₆ (%) MS (m / z) SI-MS, Pos: 377 (M + H) IR (nujol) cm ^-1 : 1655,1600,1310,1280,1080,970,75
0,710 ¹ H-NMR (DMSO-d ₆ ) δppm: 1.56 (2H, m), 1.78 (2H, m),
2.49 (2H, m), 2.60 (8H, s), 2.95 (2H, t, J = 7.2), 4.38
(1H, s), 7.28 (2H, t, J = 7.0), 7.39 (2H, t, J = 7.2), 7.52
(2H, d, J = 7.6) Example 19 1-[(4-chlorophenyl) phenylmethyl] -4- [3
-(1H-Tetrazol-5-yl) propyl] piperazine dihydrochloride

[Chemical formula 26] Melting point 198-203 ℃ MS (m / z) SI-MS, Pos: 397 (M + H), 201, 166 Elemental analysis As C ₂₁ H ₂₇ N ₆ Cl ₃ (%) IR (nujol) cm ^-1 : 1550,1095,1020,760,730 ¹ H-NMR (DMSO-d ₆ ) δppm: 2.13 (2H, m), 2.98 (2H, t, J =
7.0), 3.35 (4H, m), 3.63 (4H, m), 5.53 (1H, brs), 7.2
-8.1 (9H, m) Example 20 1- [Bis (4-fluorophenyl) methyl] -4- [3-
(1H-Tetrazol-5-yl) propyl] piperazine

[Chemical 27] Melting point 170-172 ℃ MS (m / z) SI-MS: 399 (M + H), 203 Elemental analysis As C ₂₁ H ₂₄ F ₂ N ₆ (%) IR (nujol) cm ^-1 : 2100,1600,1500,1400,1300,1225,109
0,970,870,830,725 ¹ H-NMR (DMSO-d ₆ ) δppm: 1.85 (2H, m), 2.50 (10H,
m), 2.86 (2H, t, J = 7.3), 4.36 (1H, s), 7.12 (4H, t, J = 8.
9), 7.43 (4H, dd, J = 8.2,5.9) Example 21 4-Benzhydryloxy-1- [3- (1H-tetrazol-5-yl) propyl] -piperidine

[Chemical 28] 4- (4-benzhydryloxypiperidin-1-yl) butyronitrile synthesized in the same manner as in Example 20 (2 g, 5.3 mm
ol) and tributyltin azide (3.35 g, 10.6 mmol) were stirred in dimethoxyethane (DME) at 90 ° C. for 48 hours.
Water was added to the reaction solution, and ethyl acetate (20 ml) and hexane (100 ml) were further added. The precipitated crystals were collected by filtration and recrystallized from chloroform-ether to give the title compound (1.8 g, yield 80%).

Melting point 216-217 ° C MS (m / z) SI-MS, Pos: 378 (M + H), 167,133 Elemental analysis as C ₂₂ H ₂₇ N ₅ O (%) IR (nujol) cm ^-1 : 1500,1400,1300,1260,1220,1110,1
060,960,745,705 ¹ H-NMR (DMSO-d ₆ ) δppm: 1.47 (2H, m), 1.96 (4H, m),
2.49 (2H, t, J = 9.5), 2.68 (2H, t, J = 6.7), 2.93 (4H,
m), 5.73 (1H, s), 7.31 (2H, t, J = 6.1), 7.43 (8H, m) Example 22 4-[(4-chlorophenyl) phenylmethoxy] -1-
[3- (1H-tetrazol-5-yl) propyl] piperidine

[Chemical 29] 4- {4-[(4-chlorophenyl) phenylmethoxy] piperidin-1-yl} obtained in the same manner as in Example 1
Butyronitrile (1.7 g, 4.6 mmol) and tributyltin azide
(2.87 g, 9.2 mmol) in dimethoxyethane (DME)
The mixture was stirred at 0 ° C for 48 hours. Acetonitrile (1
0 ml) was added and the mixture was further stirred for 6 hours at 90 ° C. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, and the crystals were washed with chloroform-
Recrystallization from ether gave the title compound (1.3 g, yield 69%).

Melting point: 210-213 ° C. MS (m / z) SI-MS: 412 (M + H), 201,165 Elemental analysis As C ₂₂ H ₂₆ ClN ₅ O (%) IR (nujol) cm ^-1 : 1495,1400,1300,1090,1055,750,71
0 ¹ H-NMR (DMSO-d ₆ ) δppm: 1.75 (2H, m), 1.99 (4H, m),
2.61 (2H, m), 2.76 (2H, t, J = 6.9), 2.93 (2H, t, J = 7.
3), 3.01 (2H, m), 5.73 (1H, s), 7.44 (9H, m) Example 23 4- [bis (4-fluorophenyl) methoxy] -1-
[3- (1H-tetrazol-5-yl) propyl] piperidine

[Chemical 30] Colorless powder MS (m / z) SI-MS, Pos: 414 (M + H), 203 Elemental analysis As C ₂₂ H ₂₅ N ₅ O ₂ F ₂ (%) Hydrochloride IR (nujol) cm ⁻¹ : 1500,1400,1260,1120,970,830,725 ¹ H-NMR (DMSO-d ₆ ) δppm: 1.95 (2H, m), 2.16 (4H, m),
2.92 (8H, m), 3.52 (1H, m), 5.70 (1H, s), 7.15 (4H,
m), 7.40 (4H, m) Example 24 4-[(4-chlorophenyl) phenylmethoxy] -1
-[4- (1H-tetrazol-5-yl) butyl] piperidine

[Chemical 31] Colorless powder FAB-MS (m / z) 425 (M + 1), 278, 202, 187 IR (nujol) cm ^-1 : 1500,1400,1260,1120,970,830,725 ¹ H-NMR (DMSO-d ₆ ) δppm: 7.2-7.4 (9H, m), 5.62 (1H,
s), 3.38 (1H, m), 2.84 (2H, t, J = 6), 2.73 (2H, m), 2.3
7 (2H, t, J = 6), 2.16 (2H, m), 1.4-2.0 (8H, m) Example 25 4-[(4-chlorophenyl) phenylmethylene] -1
-[3- (1H-tetrazol-5-yl) propyl]
Piperidine

[Chemical 32] Colorless powder MS (m / z) SI- MS, Pos: 393 (M + H), as 360,296,140 elemental analysis _{C 22 H 23 N 5 · 1.5H} 2 O (%) IR (KBr) cm ^-1 : 3435,2565,1487,1089,1031,964,825,
763,703,509 ¹ H-NMR (CDCl ₃ ) δppm: 7.32 (5H, m), 7.18 (4H, m),
3.20 (4H, m), 3.09 (4H, m), 2.87 (4H, m), 2.23 (2H, t,
J = 6) Example 26 4- (dibenzo [a, d] cycloheptan-5-yl)
-1- [3- (1H-tetrazol-5-yl) propyl] piperazine dihydrochloride

[Chemical 33] White amorphous MS (m / z) SI-MS, Pos: 389 (M + H), 194,178,114 Elemental analysis C ₂₄ H ₃ 0N ₆ 2HCl ・ H ₂ O (%) IR (KBr) cm ^-1 : 2997,2725,2584,1635,1560,1442,141
9,1076,906,630 ¹ H-NMR (CDCl ₃ ) δppm: 7.35 (8H, m), 5.21 (1H, brs),
3.90 (2H, m), 3.37 (2H, brt), 3.27 (2H, t, J = 6), 3.08
(4H, m), 2.31 (2H, m) Example 27 4- (dibenzo [a, d] cycloheptan-5-yl)
-1- [4- (1H-tetrazol-5-yl) butyl] piperazine dihydrochloride

[Chemical 34] White amorphous MS (m / z) SI-MS, Pos: 403 (M + H), 193 Elemental analysis C ₂₄ H ₃ 0N ₆・ 2HCl ・ 0.5H ₂ O (%) IR (KBr) cm ^-1 : 2960,1564,1446,1396,1058,773,744 ¹ H-NMR (CDCl ₃ ) δppm: 7.38 (4H, m), 7.27 (4H, m),
5.21 (1H, brs), 3.91 (2H, m), 3.39 (2H, m), 3.22 (6H,
m), 3.01 (4H, m), 1.87 (4H, m) Example 28 4- (6H-dibenzo [b, e] oxepin-11-yl) -1- [3- (1H-tetrazol-5-yl) ) Propyl] piperazine

[Chemical 35] White amorphous MS (m / z) FAB-MS, Pos: 391 (M + H), 195 IR (KBr) cm ^-1 : 3389,2869,1606,1574,1478,1456,125
5,1228,1109,1004,761,725,638 ¹ H-NMR (CDCl ₃ ) δppm: 7.30 (4H, m), 7.15 (2H, t, J =
7.5), 6.82 (2H, t, J = 7.5), 6.72 (1H, d, J = 11.5), 4.73
(1H, d, J = 11.9), 4.03 (1H, s), 3.09 (2H, m), 2.73 (8H,
m), 1.9-2.1 (2H, m) Example 29 4- (dibenzo [a, d] cyclohepten-5-yl)
-1- [3- (1H-tetrazol-5-yl) propyl] piperidine

[Chemical 36] White amorphous MS (m / z) FAB-MS, Pos: 387 (M + H), 191 IR (KBr) cm ^-1 : 3392,1645,1436,1402,1276,1103,97
3,796,763,730,628,493, ¹ H-NMR (CDCl ₃ ) δppm: 7.37 (8H, m), 6.94 (2H, s),
4.48 (1H, s), 3.18 (2H, t-like), 2.73 (2H, t-like),
2.69 (4H, m), 2.29 (4H, m), 1.95 (2H, m) Example 30 4- (Dibenzo [a, d] cyclohepten-5-yl)
-1- [4- (1H-tetrazol-5-yl) butyl] piperidine

[Chemical 37] White amorphous MS (m / z) FAB-MS, Pos: 401 (M + H), 191 IR (KBr) cm ^-1 : 3045,2871,1635,1436,1402,1247,110
3,997,798,763,730,464, ¹ H-NMR (CDCl ₃ ) δppm: 7.31 (8H, m), 6.94 (2H, S),
4.40 (1H, s), 2,92 (2H, t, J = 6.0), 2.64 (6H, m), 2.28
(4H, t, J = 4.6), 1.78 (2H, m), 1.63 (2H, m) Example 31 4- (6H-dibenzo [b, e] oxepin-11-yl) -1- [4- ( 1H-tetrazol-5-yl) butyl] piperazine

[Chemical 38] White amorphous MS (m / z) FAB-MS, Pos: 405 (M + H), 195 IR (KBr) cm ^-1 : 3485,1487,1446,1255,1228,1109,100
4,765 ¹ H-NMR (CDCl ₃ ) δppm: 7.29 (6H, m), 6.82 (2H, m),
6.69 (1H, d, J = 11.5), 4.72 (1H, d, J = 11.5), 4.00 (1H,
s), 3.00 (2H, t, J = 5.6), 2.5-2.9 (10H, m), 1.87 (2H,
m), 1.71 (2H, m) Example 32 4-[(4-chlorophenyl) phenylmethylene] -1
-[4- (1H-tetrazol-5-yl) butyl] piperidine

[Chemical Formula 39] White amorphous MS (m / z) FAB-MS, Pos: 408 (M + H), 296 IR (KBr) cm ^-1 : 3438,3099,2763,2650,1487,1442,139
8,1087,1014,829,763,703 ¹ H-NMR (CDCl ₃ ) δppm: 7.26 (5H, m), 7.04 (4H, m),
3.00 (4H, t-like), 2.87 (2H, t-like), 2.70 (4H, t-lik
e), 1.83 (4H, m) Example 33 4-[(4-chlorophenyl) phenylmethylene] -1
-[3- (1H-tetrazol-5-yl) propyl]
Piperidine

[Chemical 40] White amorphous MS (m / z) FAB-MS, Pos: 393 (M + H), 296 IR (KBr) cm ^-1 : 3436,2565,1487,1089,1031,825,763,
703 ¹ H-NMR (CDCl ₃ ) δppm: 7.32 (5H, m), 7.08 (4H, m),
3.15 (6H, m), 2.87 (2H, t-like), 2.30 (2H, m) Example 34 4- [bis (4-methoxyphenyl) methylene] -1-
(Ethoxycarbonyl) piperidine

[Chemical 41] Zinc powder (40.5g, 0.62mmol) dried TH
F is suspended in 500 ml, and titanium tetrachloride (34 ml, 0.30 mol) is added dropwise at 10 ° C or lower. After drying for 0.5 hours, heat at 80 ° C for 1 hour. The reaction solution was cooled again to 0 ° C. and 4,4′-dimethoxybenzophenone (25 g,
0.103 mol), 1-ethoxycarbonylpiperidone (18 g, 0.103 mol) in THF (100 m
It was dissolved in 1) and added. Transfer the reaction mixture to an oil bath at 80 ° C.
Heat at reflux for 2 hours. The reaction mixture was cooled, poured into an aqueous solution of potassium carbonate, the THF layer was removed, and the mixture was extracted with ethyl acetate. The extracts were combined, dried and concentrated. The concentrate was subjected to silica gel chromatography and eluted with ethyl acetate-hexane (2: 8) to obtain the desired product (34 g, 94%).

Oily IR (nujol) cm ⁻¹ : 1735,1605,1578,1490,1390,1130 ¹ H-NMR (DMSO-d ₆ ) δppm: 7.01 (4H, d, J = 9), 6.82 (4
H, d, J = 9), 4.15 (2H, q, J = 7), 3.78 (6H, s), 3.49 (4H,
m), 2.35 (4H, m), 1.25 (3H, t, J = 7) Example 35 4- [bis (4-methoxyphenyl) methylene] piperidine

[Chemical 42] 4- [bis (4-methoxyphenyl) methylene] -1-
(Ethoxycarbonyl) piperidine (35 g) is dissolved in ethanol (300 ml), caustic potash (120 g) is added, and the mixture is stirred overnight. Concentrate ethanol and water (500m
1) was added, extracted with chloroform (200 ml), dried and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 20 g of the desired product.

¹ H-NMR (CDCl ₃ ) δppm: 7.01 (4H, d, J =
9), 6.82 (4H, d, J = 9), 3.78 (6H, s), 2.90 (4H, m), 2.
32 (4H, m)

[0048]

INDUSTRIAL APPLICABILITY The novel tetrazole derivative of the present invention or a salt thereof exhibits excellent antihistamine action and antiallergic action, is extremely effective for both asthma of immediate reaction and delayed reaction, and has central inhibitory action. There are few side effects such as. The novel tetrazole derivative or a salt thereof of the present invention is also useful as a therapeutic agent for rhinitis, a therapeutic agent for nephritis, a therapeutic agent for atopic dermatitis and a therapeutic agent for psoriasis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/55 ACD 9454-4C C07D 257/04 C 405/12 257 405/14 211 409/12 257 409/14 211 495/04 101 111 // (C07D 401/06 211: 00 257: 00) (C07D 405/14 211: 00 257: 00 311: 00) (C07D 405/14 211: 00 257: 00 313 : 00) (C07D 409/14 211: 00 257: 00 333: 00) (C07D 409/14 211: 00 257: 00 335: 00) (C07D 495/04 311: 00 333: 00) (C07D 495/04 313: 00 333: 00) (C07D 495/04 333: 00 335: 00) (72) Inventor Kazuhiko Mitsui 4-533 Kitahama, Chuo-ku, Osaka City, Osaka Prefecture Sumitomo Metal Industries, Ltd.

Claims (2)

[Claims] 1. The following formula (1): [In the formula, A _{-CH = CH -, - CH 2} -CH 2 -, - C
H ₂ O-, an oxygen atom or a sulfur atom, or when A is not linked to an aromatic ring, A represents a hydrogen atom bonded to each aromatic ring; V represents -CH = CH- or a sulfur atom. Xa and Y are each independently an alkoxy group, a halogen atom or a hydrogen atom; (a) W is a bond, Z is a carbon atom or methine, B is a bond with Z or represents a hydroxy group, Alternatively, (b) W is a bond, Z is a nitrogen atom, B is a hydrogen atom, or (c) W is an oxygen atom, Z is methine, and B is a hydrogen atom; p is an integer of 2 to 3; And n is 1
Represents an integer of 6] or a pharmacologically acceptable salt thereof. 2. The following formula (1): [In the formula, A _{-CH = CH -, - CH 2} -CH 2 -, - C
H ₂ O-, an oxygen atom or a sulfur atom, or when A is not linked to an aromatic ring, A represents a hydrogen atom bonded to each aromatic ring; V represents -CH = CH- or a sulfur atom. Xa and Y each independently represent an alkoxy group, a halogen atom or a hydrogen atom; (a) W is a bond, Z is a carbon atom or methine, B is a bond with Z or represents a hydroxy group, Alternatively, (b) W represents a bond, Z represents a nitrogen atom, B represents a hydrogen atom, or (c) W represents an oxygen atom, Z represents methine, and B represents a hydrogen atom; p represents an integer of 2 to 3; And n is 1
Represents an integer of 6], an antihistamine agent, an antiallergic agent and a therapeutic agent for asthma containing a tetrazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.